Numerous cytokines participate in inflammation; among the most important regulators of this process are tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1). TNF-a and IL-1 are produced primarily by cells of the monocyte-macrophage lineage. They work in concert to stimulate inflammatory responses such as pain, fever, and the recruitment of lymphocytes. In addition, they induce production of many other inflammatory mediators and contribute to the tissue damage seen in chronic inflammation.
TNF-a and IL-1 are current targets of antiinflammatory drug therapy. A homotrimer of 17-kDa protein subunits whose effects include the activation of neu-trophils and eosinophils, induction of COX-2, induction of proinflammatory cytokines (e.g., IL-1, IL-6), enhancement of endothelial layer permeability, induction of adhesion molecules by endothelial cells and leukocytes, stimulation of fibroblast proliferation, degradation of cartilage, and stimulation of bone reabsorption. Two receptors mediate these effects: a 55-kDa receptor (p55) and a 75-kDa receptor (p75). Each of these receptors is found in both cell surface and soluble forms. The binding of two or three cell surface receptors to TNF-a initiates an inflammatory response. Soluble p55 also acts as a signaling receptor for inflammatory responses, whereas soluble p75 acts as an antagonist.
IL-1 occurs as two polypeptides, IL-1a and IL-1p, and produces many of the same effects as TNF-a. An 80-kDa type 1 IL-1 receptor and a 68-kDa type 2 IL-1 receptor found on the surface of some cell types bind both forms of IL-1. An endogenous 17-kDa IL-1 receptor antagonist (IL-1ra) competes for binding with IL-1 and counterbalances the inflammatory response.
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